2. Academic Validation
  3. Discovery of Nanomolar DCAF1 Small Molecule Ligands

Discovery of Nanomolar DCAF1 Small Molecule Ligands

  • J Med Chem. 2023 Apr 13;66(7):5041-5060. doi: 10.1021/acs.jmedchem.2c02132.
Alice Shi Ming Li 1 2 3,  Serah Kimani 1 4,  Brian Wilson 2,  Mahmoud Noureldin 2 3,  Héctor González-Álvarez 2 3,  Ahmed Mamai 2,  Laurent Hoffer 2,  John P Guilinger 5,  Ying Zhang 5,  Moritz von Rechenberg 6,  Jeremy S Disch 6,  Christopher J Mulhern 6,  Belinda L Slakman 6,  John W Cuozzo 6,  Aiping Dong 1,  Gennady Poda 2 7,  Mohammed Mohammed 2,  Punit Saraon 2,  Manish Mittal 8,  Pratik Modh 8,  Vaibhavi Rathod 8,  Bhashant Patel 8,  Suzanne Ackloo 1,  Vijayaratnam Santhakumar 1,  Magdalena M Szewczyk 1,  Dalia Barsyte-Lovejoy 1 3,  Cheryl H Arrowsmith 1 4 9,  Richard Marcellus 2,  Marie-Aude Guié 5,  Anthony D Keefe 5,  Peter J Brown 1,  Levon Halabelian 1 3,  Rima Al-Awar 2 3 10,  Masoud Vedadi 1 2 3
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 2 Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
  • 3 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 4 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C1, Canada.
  • 5 X-Chem Inc., Waltham, Massachusetts 02453, United States.
  • 6 Relay Therapeutics, Cambridge, Massachusetts 02139, United States.
  • 7 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
  • 8 Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Ahmedabad, Gujarat 382213, India.
  • 9 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 10 Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada.
PMID: 36948210 DOI: 10.1021/acs.jmedchem.2c02132
Abstract

DCAF1 is a substrate receptor of two distinct E3 Ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 μM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 μM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward Cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

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